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Retrospective Characterization of Genetics Work-Up for Individuals with RASopathy Diagnosis

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
The RASopathies are a group of heterogenous conditions caused by pathogenic variants in genes of the RAS/mitogen-activated protein kinase (MAPK) pathway. RASopathies are estimated to have a prevalence of 1 in 1000 live births and confirming an early diagnosis allows for tailored management and treatment of clinical manifestations. This retrospective chart review characterizes the genetic testing work-up for individuals with a RASopathy diagnosis at a large, metropolitan academic medical center.

Methods:
This study was approved by Lurie Children’s Hospital Institutional Review Board (IRB 2023-5909). It includes data available from 2006 to 2024 for individuals with a molecularly confirmed or clinically suspected RASopathy diagnosis identified through an internal database and secondarily verified in the institutional electronic medical record. Clinical data was abstracted from medical records and entered in a secure database for analysis including demographic information, age at time of RASopathy diagnosis, genetic testing ordered and indication, and testing outcome. Analysis of data included descriptive statistics and two-tailed T-test.

Results:
This study identified 131 individuals with a molecularly confirmed or clinically suspected RASopathy diagnosis. In this cohort, sex assigned at birth is 56% male. Reported race and ethnicity is 46% White/Non-Hispanic, 22% Other/Hispanic, 11% Black/Non-Hispanic, 9% White/Hispanic, and 5% Other/Non-Hispanic, 4% Asian/Non-Hispanic, and 3% Other Race/Ethnicity. Preferred language is 82% English. Insurance is 57% private and 43% Medicaid.

A RASopathy diagnosis was molecularly confirmed in 116 individuals (88.5%) and there is no molecularly confirmed diagnosis for 15/131 (11.5%) individuals. Four of 131 (3.1%) individuals have dual genetic diagnoses. The average age at molecular diagnosis was 5 years (range: prenatal to 41 years). A total of 193 tests were performed in this cohort with an average of 2 tests per patient (range: 1-9 tests). Most individuals (72/131, 55%) were diagnosed with the first test ordered by the provider evaluating the initial presentation. A small subset of individuals required more than 4 tests to achieve a diagnosis (2/131, 1.4%). Race, ethnicity, nor language had a statistically significant impact on number of tests completed to reach RASopathy diagnosis. Diagnostic yields of top-ordered tests in this cohort of individuals are exome (96.8%), Noonan/RASopathy panel (87.5%), genome (71.4%), and cardiac panel (62.5%).

The most common tests ordered in individuals with diagnosis after 1 test were Noonan/RASopathy panel (N=34), followed by exome (N=14), familial testing (N=10), cardiac panel (N=6), genome (N=4), PTPN11 gene analysis (N=2), cancer gene panel (N=1), and unspecified panel (N=1).

The most common test ordered in individuals with diagnosis after 2 tests was exome (N=12), with diagnosis after 3 tests was Noonan/RASopathy panel (N=12), with diagnosis after 4 tests was exome (N=1).

The individual who was diagnosed after 9 tests was diagnosed by a cardiac panel. This individual never had a Noonan/RASopathy panel or exome ordered, however symptoms were non-specific including developmental delays and mitral valve prolapse.

Conclusion:
The majority of individuals in this cohort did have a molecular diagnosis confirmed which demonstrates the remarkable advance in the molecular understanding of RASopathies. The most commonly ordered test was Noonan/RASopathy panel. Exome testing was the second most common test leading to diagnosis with utilization increasing over time. Of note, exome had a higher diagnostic yield than Noonan/RASopathy panel. This could be due to ongoing discovery of new genes in the RASopathy pathway and ability of exome to incorporate candidate genes and non-specific clinical indications whereas a panel is curated and updates may be delayed. Exome should be considered an alternative first-tier testing to a Noonan/RASopathy panel when there is suspicion for a RASopathy diagnosis in order to improve diagnostic yield and timely diagnosis.

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